Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element

Serene Keilani, Samira Chandwani, Georgia Dolios, Alexey Bogush, Heike Beck, Antonis K. Hatzopoulos, Gadiparthi N. Rao, Elizabeth A. Thomas, Rong Wang, Michelle E. Ehrlich

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17 Scopus citations

Abstract

DARPP-32 (dopamine and adenosine 3′, 5′-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), aknown inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, over expression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominant-negative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation.

Original languageEnglish
Pages (from-to)6808-6818
Number of pages11
JournalJournal of Neuroscience
Volume32
Issue number20
DOIs
StatePublished - 16 May 2012

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